Tacrolimus (TAC), also called FK506, is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation. However, it has been proved to be associated with post-transplant hyperlipemia. The mechanism behind this is unknown, and it is urgent to explore preventive strategies for hyperlipemia after transplantation. Therefore, we established a hyperlipemia mouse model to investigate the mechanism, by injecting TAC intraperitoneally for eight weeks. After TAC treatment, the mice developed hyperlipemia (manifested as elevated triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c), as well as decreased high-density lipoprotein cholesterol (HDL-c)). Accumulation of lipid droplets was observed in the liver. In addition to lipid accumulation, TAC induced inhibition of the autophagy-lysosome pathway (microtubule-associated protein 1 light chain 3β (LC3B) II/I and LC3B II/actin ratios, transcription factor EB (TFEB), protein 62 (P62), and lysosomal-associated membrane protein 1 (LAMP1)) and downregulation of fibroblast growth factor 21 (FGF21) in vivo. Overexpression of FGF21 may reverse TAC-induced TG accumulation. In this mouse model, the recombinant FGF21 protein ameliorated hepatic lipid accumulation and hyperlipemia through repair of the autophagy-lysosome pathway. We conclude that TAC downregulates FGF21 and thus exacerbates lipid accumulation by impairing the autophagy-lysosome pathway. Recombinant FGF21 protein treatment could therefore reverse TAC-caused lipid accumulation and hypertriglyceridemia by enhancing autophagy.
他克莫司（TAC），也称为FK506，是预防肝移植后同种异体移植排斥反应的经典免疫抑制剂之一。然而，它已被证明与移植后高脂血症有关。但其背后的机制尚不清楚，因此迫切需要探索移植后高脂血症的预防策略。我们通过腹腔注射8周TAC建立了一个高脂血症小鼠模型来研究其机制。TAC处理后，小鼠发生高脂血症（表现为甘油三酯（TG）和低密度脂蛋白胆固醇（LDL-c）升高，以及高密度脂蛋白胆固醇（HDL-c）降低）以及肝脏脂质的累积。除脂质积累外，TAC还抑制了自噬-溶酶体途径（LC3B II/I和LC3BII/actin比值、转录因子EB（TFEB）、P62和LAMP1），并下调成纤维细胞生长因子21（FGF21）的表达。而FGF21的过表达可逆转TAC诱导的TG积累。在该小鼠模型中，重组FGF21蛋白通过修复自噬-溶酶体途径改善肝脏脂质积累和高脂血症。综上所述，TAC下调FGF21，从而通过抑制自噬-溶酶体途径来加剧脂质积累。此外，重组FGF21蛋白处理可以通过增强自噬来逆转TAC引起的脂质积累和高甘油三酯血症。.
他克莫司（TAC），也称为FK506，是预防肝移植后同种异体移植排斥反应的经典免疫抑制剂之一。然而，它已被证明与移植后高脂血症有关。但其背后的机制尚不清楚，因此迫切需要探索移植后高脂血症的预防策略。我们通过腹腔注射8周TAC建立了一个高脂血症小鼠模型来研究其机制。TAC处理后，小鼠发生高脂血症（表现为甘油三酯（TG）和低密度脂蛋白胆固醇（LDL-c）升高，以及高密度脂蛋白胆固醇（HDL-c）降低）以及肝脏脂质的累积。除脂质积累外，TAC还抑制了自噬-溶酶体途径（LC3B II/I和LC3BII/actin比值、转录因子EB（TFEB）、P62和LAMP1），并下调成纤维细胞生长因子21（FGF21）的表达。而FGF21的过表达可逆转TAC诱导的TG积累。在该小鼠模型中，重组FGF21蛋白通过修复自噬-溶酶体途径改善肝脏脂质积累和高脂血症。综上所述，TAC下调FGF21，从而通过抑制自噬-溶酶体途径来加剧脂质积累。此外，重组FGF21蛋白处理可以通过增强自噬来逆转TAC引起的脂质积累和高甘油三酯血症。
Keywords: Autophagy; Fibroblast growth factor 21 (FGF21); Lipid; Lipophagy; Lysosome; Tacrolimus; Transcription factor EB (TFEB).